Loop propensity of the sequence YKGQP from staphylococcal nuclease: implications for the folding of nuclease

Abstract

Recently we performed molecular dynamics (MD) simulations on the folding of the hairpin peptide DTVKLMYKGQPMTFR from staphylococcal nuclease in explicit water. We found that the peptide folds into a hairpin conformation with native and nonnative hydrogen-bonding patterns. In all the folding events observed in the folding of the hairpin peptide, loop formation involving the region YKGQP was an important event. In order to trace the origins of the loop propensity of the sequence YKGQP, we performed MD simulations on the sequence starting from extended, polyproline II and native type I' turn conformations for a total simulation length of 300 ns, using the GROMOS96 force field under constant volume and temperature (NVT) conditions. The free-energy landscape of the peptide YKGQP shows minima corresponding to loop conformation with Tyr and Pro side-chain association, turn and extended conformational forms, with modest free-energy barriers separating the minima. To elucidate the role of Gly in facilitating loop formation, we also performed MD simulations of the mutated peptide YKAQP (Gly --> Ala mutation) under similar conditions starting from polyproline II conformation for 100 ns. Two minima corresponding to bend/turn and extended conformations were observed in the free-energy landscape for the peptide YKAQP. The free-energy barrier between the minima in the free-energy landscape of the peptide YKAQP was also modest. Loop conformation is largely sampled by the YKGQP peptide, while extended conformation is largely sampled by the YKAQP peptide. We also explain why the YKGQP sequence samples type II turn conformation in these simulations, whereas the sequence as part of the hairpin peptide DTVKLMYKGQPMTFR samples type I' turn conformation both in the X-ray crystal structure and in our earlier simulations on the folding of the hairpin peptide. We discuss the implications of our results to the folding of the staphylococcal nuclease.

A shorter peptide model from staphylococcal nuclease for the folding–unfolding equilibrium of a β-hairpin shows that unfolded state has significant contribution from compact conformational states

“…The same YP contact is also observed in the simulation of shorter pentapeptide YKGQP (Patel and Sasidhar, 2007). Consolidation of hydrophobic interactions and subsequent formation of hydrogen bonds are also common to both LMYKGQPM and DTVKLMYKGQPMTFR peptides suggesting that in both the cases local interactions involved in the loop formation are guiding the process of folding.…”

Molecular dynamics simulations of certain mutant peptide models from staphylococcal nuclease reveal that initial hydrophobic collapse associated with turn propensity drives β‐hairpin folding

“…List of the turn propensities (in %) for the 5mer peptides in terms of Ca atom distance between residues Y2 (or G2) and Q5 (or G5) and hydrogen-acceptor distance for the turn hydrogen bonds Q5/G5:H-Y2/G2:O and Y2/G2:H-Q5/G5:O. The turn propensity of the wt turn sequence 'YKGQP' is also mentioned [5] 5Mer peptide systems Ca (Y2/G2)-Ca (Q5/G5) distance ≤ 0.7 nm Q5 Figure 3. Projection of the calculated free energy along eigenvector 1 for K3G:5 mutant, A; for Q5G:5 mutant peptide, B; for K3G/Q5G:5 mutant peptide, C; and for the penta-G:5 peptide, D. The representative conformations corresponding to each minimum are also indicated.…”

“…The study also suggests the importance of Y8‐P12 side‐chain interaction in the formation of β ‐turn between residues Y8 and Q11 in the folding of β ‐hairpin. Another simulation study on the turn sequence Ac‐ 2 YKGQP 6 ‐NMe and its variant Ac‐ 2 YKAQP 6 ‐NMe suggests that glycine at position i + 2 is crucial for the turn propensity of the peptide . YKGQP peptide shows a much higher propensity to form a β ‐turn compared with the variant peptide YKAQP.…”

Conformational dynamics of a short antigenic peptide in its free and antibody bound forms gives insight into the role of β‐turns in peptide immunogenicity

“…The number of points occupying ith cell was referred to as N i . The free energy of each cell was calculated for the free Ag‐extended and the bound Ag–Ab systems using the following equation …”